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United States Patent | 5,719,273 |
Tu ,   et al. | February 17, 1998 |
This invention discloses a method for the preparation modified nucleosides using a palladium catalyst, a nucleophile and carbon monoxide.
Inventors: | Tu; Chi (Louisville, CO); Dewey; Torin M. (Boulder, CO); Eaton; Bruce (Boulder, CO) |
Assignee: | NeXstar Pharmaceuticals, Inc. (Boulder, CO) |
Appl. No.: | 458421 |
Filed: | June 2, 1995 |
Current U.S. Class: | 536/27.6; 536/27.61; 536/27.62; 536/27.8; 536/27.81; 536/28.5; 536/28.51; 536/28.52; 536/28.53; 536/28.54; 536/28.55 |
Intern'l Class: | C07H 019/00 |
Field of Search: | 536/28.1,28.4,28.5,28.51,28.52,28.53,28.54,27.6,27.61,27.62,27.8,27.81 |
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WO 91/06629 | May., 1991 | WO. | |
WO 91/10671 | Jul., 1991 | WO. | |
WO 91/14696 | Oct., 1991 | WO. |
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TABLE I __________________________________________________________________________ Examples of modified purine nucleosides. Amine Nucleophile Product Isolated Entry Nucleoside H.sub.2 NR ID Yield (%) __________________________________________________________________________ 1 1 4 .sup. 87.sup.b 2 1 ##STR11## 5 95 3 2 ##STR12## 6 93 4 2 ##STR13## 7 .sup. 84.sup.a 5 2 ##STR14## 8 95 6 2 ##STR15## 9 98 7 2 ##STR16## 10 41 8 2 ##STR17## 11 91 9 2 ##STR18## 12 .sup. 62.sup.c 10 2 ##STR19## 13 71 11 3 ##STR20## 14 85 12 3 ##STR21## 15 98 13 3 ##STR22## 16 88 14 3 ##STR23## 17 81 15 3 ##STR24## 18 56 __________________________________________________________________________ .sup.a The reaction produced 16% of direct coupling side product. .sup.b The reaction produced 15% of direct coupling side product. .sup.c The reaction produced 14% of direct coupling side product and 14% of ester.
TABLE II ______________________________________ Summary of uridine carboxyamidation products. Nucleoside starting Isolated Yield Entry material RYH Product ID (%) ______________________________________ 1 19 A 22 65% 2 19 B 23 89% 3 19 C 24 20% 4 19 D 25 78% 5 20 E 26 <20% 6 21 E 27 <20% 7 20 F 28 69% 8 21 G 29 68% 9 21 H 30 57% ______________________________________ Starting Material Syntheses.